Download Safety and Efficacy Results of a Phase 2 Randomized, Placebo

Safety and Efficacy Results of a Phase 2 Randomized,
Placebo-Controlled, Dose-Ranging Study of ELND005
(Scyllo-inositol) in Mild to Moderate Alzheimer’s Disease
1Stephen
Salloway MD, 2Anton Porsteinsson MD, 3Reisa Sperling MD, 4Ron Keren MD, 5Christopher Van Dyck MD,
Tariot MD, 7Sid Gilman MD, 8Gerald Crans PhD, 8Chito Hernandez PhD, 8Grainne Quinn MD, 8Menghis Bairu
MD, 8Jesse Cedarbaum MD, 9Aleksandra Pastrak MD, PhD, 8Susan Abushakra MD
6Pierre
1Butler
Hospital, Brown University; 2University of Rochester Medical Center, Monroe Community Hospital; 3Brigham and Women's Hospital ;
Shores Centre for Mental Health Sciences; 5Yale University School of Medicine; 6Banner Alzheimer's Institute; 7University of
Michigan; 8Elan Pharmaceuticals, Inc; 9Transition Therapeutics Inc
4Ontario
BACKGROUND
• In preclinical studies, ELND005 (Scyllo-inositol) was shown to be an Aβ aggregation inhibitor that breaks down Aβ fibrils,
and inhibits aggregation and Aβ oligomer-induced neurotoxicity
• Loss of Cognitive and Functional Abilities
• Emergence of Behavioral Symptoms
• In preclinical studies ELND005 has shown the following effects:
• Aβ anti-aggregation effects in vitro (McLaurin et al, J Biol Chem 2000;275:18495-502)
• Protection from Aβ oligomer induced LTP inhibition and dendritic spine loss (Shankar et al, J Neurosci 2007;27:2866-75;
Townsend et al, Ann Neurol 2006;60:668-76)
• In TgCRND8 mice (McLaurin et al., Nature Med 2006;12:801) :
– Decrease in amyloid burden, vascular amyloid, astrocytosis, and microgliosis
– Improvement in Morris Water Maze performance, with early and late intervention models
• This 78-week, Phase 2 study evaluated efficacy and safety of 3 ELND005 doses; CSF and MRI biomarkers were included to
support a potential disease modifying profile (to be presented on Wednesday July 20)
METHODS
• Randomized, placebo-controlled, parallel-arm study at 58 N. American sites
• ELND005 doses: 250mg bid, 1000mg bid, 2000mg bid and placebo
• 353 mild to moderate AD patients enrolled for treatment duration of 18 months
• AT 85 per arm (target enrollment= 340) study was powered to detect mean differences of 0.2 on NTB and 4 points on
ADCS-ADL; target enrollment 340
• The primary efficacy analysis was based on 250-mg bid and placebo groups (Mixed Effect Repeated Measure method)
• Stratification by ApoE4 carrier status & AD severity (Mild: 22-26, Moderate (16-21)
• Co-primary efficacy endpoints: NTB and ADCS-ADL
• Secondary efficacy endpoints: CDR-SB, ADAS-Cog, NPI; MMSE (exploratory endpoint)
• Pre-planned subgroup analyses:
– Mild (23-26) and Moderate (16-22) subgroups
– ApoE4 carrier vs. non-carrier
• There was no correction for multiplicity testing in the secondary/exploratory analyses
RESULTS
Study Populations and Demographics
Table 1: Demographics of Randomized Patients
Placebo
N=83
250 mg BID
N=88
1000 mg BID
N=89
2000 mg BID
N=91
73.4 / 75
73.4 / 74.5
73.4 / 75
72.2 / 74
Gender (% female)
57%
58%
54%
56%
Race (% Caucasian)
98%
97%
97%
96%
AD duration (yrs, mean/med)
4/4
4/3
4/4
4/3
ApoE4 Carrier
64%
62.5%
63%
64%
MMSE (mean/med)
20.5 / 21
20.6 / 21
20.4 / 20
20.5 / 20
% Mild (MMSE 22-26)
45%
43%
40%
43%
% Moderate (MMSE 16-21)
54%
57%
60%
57%
Education (yrs, mean/med)
14 / 14
14 / 13
14 / 14
14 / 14
94%
91%
88%
90%
Age (mean/med)
AD medication
• Randomized: N=353; safety population: N=351; modified intent-to-treat (m-ITT): N=341;
per protocol set (PPS): N=130; PPS = study completers who received at least 80% of study drug
Study AD201 Overview of Clinical Results
• Mild/Moderate (M/M) study population did not achieve significance on co-primary endpoints of NTB in m-ITT
or PPS (see Table 2 and figure 1)
• Moderate AD group (MMSE 16-22, inclusive) and ApoE4 carriers and non-carriers showed no consistent
positive or negative trends. Moderate AD results were similar in m-ITT/PPS
• Mild AD group (MMSE 23-26, inclusive) showed encouraging trends on NTB, CDR-SB, and ADCS-ADL, but not
on ADAS-cog, details shown in figures 2-5
RESULTS
Results of Mild/Moderate & Moderate Groups
Figure 1: Clinical Outcomes in Overall M/M, PPS (N=47/49)
(NTB: Δ=0.15, p=0.17; ADCS: Δ=0.65, p=0.77)
Study ELND005-AD201 Test Score Least Squares Mean Changes over Time by Treatment Group
All Subjects in PPS Population
Table 2: Clinical Outcomes in Overall M/M and Moderate AD
(m-ITT Analysis)
Decline
Improvement
Population
N= Pbo/250mg
NOTE: Change is calculated such that decreases from baseline always represent cognitive decline
NTB
ADCSADL
CDR-SB
ADAScog
Overall
Mild/Moderate
N=82/84
Δ= 0.03
P = 0.71
Δ=-1.40
P = 0.49
Δ= 0.29
P = 0.54
Δ=- 2.56
P = 0.18
Moderate
N=48/47
Δ= -0.10
P = 0.39
Δ=-4.3
P = 0.10
Δ= -0.20
P = 0.76
Δ=- 1.28
P = 0.61
RESULTS
Results of Pre-Specified Mild Group
Figure 2: Results of NTB (left) and ADCS-ADL (right)
m-ITT:
pbo n= 35; 250 = 36
NTB:
Δ=0.20, p=0.11
ADCS-ADL
Δ=2.26, p=0.43
PPS:
pbo n= 22; 250 = 24
NTB:
Δ=0.40, p=0.007
ADCS-ADL
Δ=2.25, p=0.46
mITT: % drug effect relative to placebo = 71.4% on NTB; 35.3% on ADCS-ADL
PPS: % drug effect relative to placebo > 100% on NTB; 31% on ADCS-ADL
RESULTS
Results of Pre-Specified Mild Group (continued)
Decline
Improvement
Figure 3: Sub-Items of NTB (PPS)
The sub-items of Immediate Memory and Executive Function show potential drug effects
RESULTS
Results of Pre-Specified Mild Group (continued)
Figure 4: Mild AD Results of CDR-SB, m-ITT ( m-ITT: Δ=0.87, p=0.19; PPS: =0.95, p=0.20)
% drug effect relative to placebo in m-ITT =
40% and in PPS: 43%
ADNI AD
(MMSE 23-26)
The sub-items that showed potential drug
effects were: cognitive (Memory and
Orientation), and functional (Community
Affairs and Personal Care)
Figure 5: Mild AD Results of ADAS-Cog, m-ITT (m-ITT: Δ= - 4.22, p=0.11 ; PPS: =- 4.11, p=0.18)
Only 1 of 12 sub-items showed potential
benefit in favor of placebo: Word Recognition
*ADNI AD
(MMSE 23-26)
*Placebo decline is not consistent with
expected decline from ADNI Mild population
SAFETY
Overall Mild/Moderate AD
Table 3: Overview of TEAEs in Mild/Moderate AD
Placebo
n=83
250 mg BID
n=88
1000 mg BID
n=89
2000 mg BID
n=91
Any TEAE
76 (91.6%)
77 (87.5%)
78 (87.6%)
82 (90.1%)
TEAE related to study drug
28 (33.7%)
29 (33.0%)
34 (38.2%)
29 (31.9%)
D/C due to
TEAE
8 (9.6%)
9 (10.2%)
15 (16.9%)
12 (13.2%)
Severe TEAE
5 (6.0%)
10 (11.4%)
11 (12.4%)
10 (11.0%)
Life- threaten. TEAE (CTCAE)
2 (2.4%)
1 (1.1%)
0 (0%)
1 (1.1%)
11 (13.3%)
19 (21.6%)
20 (22.5%)
21 (23.1%)
2 (2.4%)
2 (2.3%)
6 (6.7%)
2 (2.2%)
0 (0%)
1 (1.1%)
5 (5.6%)
4 (4.4%)
No. Patients (%)
SAE
SAE related to study drug
Deaths*
Continued on the next slide
SAFETY
Mild/Moderate AD
Table 4: Most Common TEAEs (≥5%) by Preferred Term (PT) in M/M
ELND005
Preferred Term
Placebo
(N=83)
Fall
Diarrhea
Urinary tract infection
Depression
Nausea
Headache
Dizziness
Agitation
Fatigue
Vomiting
Confusional state
Pooled ELND005
(N=268)
250 mg BID
(N=88)
1000 mg BID
(N=89)
2000 mg BID
(N=91)
5 (6.0)
6 (7.2)
7 (8.4)
4 (4.8)
4 (4.8)
12 (14.5)
7 (8.4)
5 (6.0)
4 (4.8)
3 (3.6)
3 (3.6)
11 (12.5)
9 (10.2)
12 (13.6)
10 (11.4)
8 ( 9.1)
4 ( 4.5)
4 ( 4.5)
4 ( 4.5)
6 ( 6.8)
5 ( 5.7)
7 ( 8.0)
10 (11.2)
8 ( 9.0)
4 ( 4.5)
4 ( 4.5)
3 ( 3.4)
11 (12.4)
6 ( 6.7)
9 (10.1)
6 ( 6.7)
3 ( 3.4)
4 ( 4.5)
14 (15.4)
12 (13.2)
11 (12.1)
12 (13.2)
14 (15.4)
8 ( 8.8)
11 (12.1)
6 ( 6.6)
7 ( 7.7)
8 ( 8.8)
4 ( 4.4)
35 (13.1)
29 (10.8)
27 (10.1)
26 (9.7)
25 (9.3)
23 (8.6)
21 (7.8)
19 (7.1)
19 (7.1)
16 (6.0)
15 (5.6)
Upper respiratory tract infection
5 (6.0)
9 (10.2)
3 ( 3.4)
3 ( 3.3)
15 (5.6)
Insomnia
5 (6.0)
3 ( 3.4)
2 ( 2.2)
8 ( 8.8)
13 (4.9)
Note: Adverse
events are
presented in the
frequency that
each event was
reported in the
pooled ELND005
group. 5% is with
respect to the total
number of patients
in the safety set.
• Serious AE (SAE):
– The overall incidence of SAEs was higher in the 3 ELND005 groups: 21.6%, 22.5%, and 23.1% in the 250-mg, 1000-mg, and 2000-mg groups
than in placebo (13.3%)
– Treatment-related SAEs were highest in 1000-mg group (6.7%) versus: Placebo (2.4%), 250-mg (2.3%), and 2000-mg (2.2%) groups
– The most frequent SAEs were infections (respiratory and urinary), and were highest at 2 top doses (placebo = 1.2%, 250 mg = 1.1%, 1000 mg
= 4.5%, 2000 mg = 8.8%)
– Placebo and 250mg groups had 1 infection SAE each (Placebo: UTI, 250mg: viral infection)
• Deaths (total 10):
– The 9 deaths in the 2 high dose groups were preceded by : aspiration pneumonia/pneumonia (2/2), respiratory failure (1), sudden death in
setting of hypokalemia (1), sudden death after AD progression (1), failure to thrive/AD progression (1/1)
– 8 of 9 deaths in 2 high dose groups were patients who had Moderate AD
– 1 death in 250mg: due to frontal cerebral hemorrhage in an ApoE4 carrier, had evidence of prior hemorrhage on baseline MRI
• Vasogenic edema: None reported by local radiologist assessments
SAFETY
Mild AD
Table 5: Most Common TEAEs (≥5%) by Mild AD* by PT
Placebo
(N=45)
n (%)
4 (8.9)
2 (4.4)
250 mg BID
(N=46)
n (%)
7 (15.2)
7 (15.2)
Depression or depressive Symptoms*
4 (8.9)
6 (13.0)
Nausea
Fatigue
Urinary tract infection
Fall
Arthralgia
Pain in extremity
Headache
Hypertension
Atrial fibrillation
Cataract
1 (2.2)
2 (4.4)
4 (8.9)
2 (4.4)
2 (4.4)
1 (2.2)
7 (15.6)
1 (2.2)
3 (6.7)
3 (6.7)
5 (10.9)
5 (10.9)
5 (10.9)
3 (6.5)
3 (6.5)
3 (6.5)
3 (6.5)
3 (6.5)
2 (4.3)
2 (4.3)
Preferred Term
Diarrhea
Upper respiratory tract infection
* Safety profile of 250mg bid in the Target Mild AD population for future studies (MMSE 22-26)
CONCLUSION
SAFETY
• The safety and tolerability profile of 250-mg bid is deemed acceptable, the independent safety committee concurred with
this assessment
– The 2 high dose groups were electively discontinued due to imbalance of infections and deaths due to various causes
EFFICACY
• In Mild/Moderate group, the treatment effects were not significant (NTB or ADCS-ADL)
• In Pre-specified analyses of Mild group, there were encouraging trends on cognition (NTB: p= 0.007 in compliant
patients who completed the study)
• The positive NTB trends were observed on both memory and executive function
• In Mild AD, the ADCS-ADL and CDR-SB effects of ELND005, though not significant, were of clinically relevant magnitude:
> 30% less decline than placebo
Above results , and the CSF biomarker results, helped select an appropriate dose for further
development of ELND005 in Mild AD
ACKNOWLEDGEMENTS
We acknowledge and thank the 58 investigators, their coordinators/staff, the patients and caregivers/families for participation
in Study AD201